Trypanosoma brucei brucei, unlike the human pathogens T. b. rhodesiense and T. gambiense, is lysed by human serum. Sensitivity to human serum is the only method which allows distinction between the cattle and human African trypanosomes. We have identified two distinct trypanolytic fractions in normal human serum (NHS) which differ physically, biochemically and with regard to their inhibition by serum factors. Significantly, an HDL-like trypanolytic factor (TLF1) described by others is not active in NHS, and only becomes lytic upon inhibitor removal during isolation procedures. It is proposed to characterize to more physiologically relevant lytic factor in human serum, and to determine the mechanism(s) by which the parasites are killed. Data indicates that a mechanism of lysis may involve oxidative stress and subsequent programmed cell death, and these possibilities will be tested directly. It is further proposed to test the hypothesis that variant surface glycoprotein (the major surface protein of T. brucei) expression site associated genes (ESAGs) are involved in the sensitivity of trypanosomes to human serum will be investigated. This work may open new perspectives for the chemotherapy of trypanosomiasis. Understanding of the mechanisms of cytotoxicity and the affected metabolic pathways may provide new approaches for development of specific drugs. It will of course be of great interest to determine the molecular basis for the remarkable difference between T. brucei, and the human parasites T. gambiense and T. rhodesiense in their susceptibility to human serum.